Diabetic Pregnancy and Fetal Consequences Kari Teramo, MD, Phd* Practice Gaps 1

Article endocrinology

Diabetic Pregnancy and Fetal Consequences Kari Teramo, MD, PhD* Practice Gaps 1. There is a need for new strategies to help decrease risk of fetal and neonatal Author Disclosure complications in diabetic pregnancy. Dr Teramo has 2. While important, it can be challenging to estimate fetal weight in diabetic pregnancy. disclosed that he answers patient Abstract questions on the Perinatal morbidity and mortality, congenital malformations, abnormal fetal growth, both spontaneous and iatrogenic preterm birth, hypoxic complications, and trauma during de- NovoNordisk website. livery are increased in diabetic pregnancies. Perinatal mortality in diabetic pregnancies is This commentary does still three to five times higher than the perinatal mortality in the general population. Still- not contain births during the last weeks of pregnancy are often considered unexplained, although re- a discussion of an cent studies indicate that most of these stillbirths are caused by fetal chronic hypoxia. unapproved/ Importantly, perinatal mortality has not changed during the past 3 decades in diabetic fi investigative use of pregnancies, which emphasizes the need to nd new methods and strategies to improve perinatal outcome. Congenital malformations have decreased in pregestational diabetic a commercial product/ pregnancies because of general improvement of glycemic control among diabetic women. device. However, the rate of fetal malformations is still two to four times higher in type 1 and type 2 diabetic pregnancies than in the general population. Prepregnancy counseling decreases the risk of fetal malformations. Efforts should be made to improve the attendance of diabetic women in prepregnancy clinics. Fetal overgrowth during the last trimester of pregnancy is the most common fetal complication in diabetic pregnancies. Accurate estimation of fetal weight by ultrasound is especially difficult in macrosomic fetuses. Magnetic resonance imaging can be used to assess fetal total volume, shoulder width, and fat amount in addition to obtaining accurate pelvic measurements. More studies on the clinical use of magnetic resonance imaging in obstetrics are urgently needed. Increased fetal erythropoietin (EPO) level is an indicator of fetal chronic hypoxia, which can be detected antenatally by measuring amniotic fluid EPO concentration. Sufficiently large controlled studies are needed before amniotic fluid EPO measurement can be recommended for clinical use.

Objectives After completing this article, readers should be able to: 1. Describe the main fetal and neonatal complications in type 1 and type 2 diabetic pregnancies. 2. Explain the role of poor glycemic control in the pathogenesis of maternal and fetal complications in diabetic pregnancies. 3. Address the importance and problems in the estimation of fetal weight in diabetic pregnancies. Abbreviations 4. Discuss possible new strategies that could improve offspring outcomes in diabetic pregnancies. CI: conﬁdence interval EPO: erythropoietin FHR: fetal heart rate Introduction GDM: gestational diabetes mellitus Pregnancies complicated by maternal diabetes have major MRI: magnetic resonance imaging effects on the developing fetus throughout pregnancy. Con- OR: odds ratio genital malformations, abnormal fetal growth, hypoxic

*Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland.

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complications, and trauma during delivery are increased perinatal deaths in type 1 diabetic pregnancies. Detection in pregnancies of diabetic women. Although the exact of lethal fetal malformations by sonography decreases the pathogenetic mechanisms of fetal complications in dia- perinatal mortality by w0.5 percentage units when these betic pregnancies are not well understood in all instances, pregnancies are interrupted before 20 weeks’ pregnancy maternal hyperglycemia, and hence fetal hyperglycemia, (unpublished observation). is associated with several fetal complications (Table). In The stillbirth rate in type 1 diabetic pregnancies in- this review, early and late fetal complications, detection, creased linearly during the last weeks of pregnancy before management, and prevention in pregnancies complicated fetal electronic monitoring was available, reaching 20% at by maternal diabetes is discussed. term. (4) The pathogenesis of this increasing trend of stillbirths toward the end of pregnancy is unknown. Al- Perinatal Mortality though the stillbirth rate has been considerably lower Perinatal mortality has remained unchanged at 2% to 4% during recent decades than in the 1950s, unexplained in type 1 diabetic pregnancies during the past 30 years in stillbirths still occur during the last weeks of pregnancy most centers specializing in the care of diabetic pregnan- in pregestational diabetes pregnancies. (3) Maternal dia- cies. (1)(2)(3) Congenital malformations (30%–40% of betes remains an independent risk factor of fetal death. ’ perinatal deaths), preterm birth (20%–30%), and intra- (5) Most of the stillbirth fetuses before 32 weeks gesta- uterine hypoxia (20%–30%) are the main causes of tion are growth restricted. (3) However, in a recent birth registry study from Norway, the stillbirth rate before 37 weeks’ gestation in type 1 diabetic pregnancies did not differ from the stillbirth rate of the background population. (6) In contrast, the stillbirth rate in term pregnan- Table. Fetal and Neonatal cies was five times higher in type 1 diabetic pregnancies Consequences of Fetal than in the general population. Also infant deaths during the first year after birth was higher in type 1 diabetes Hyperglycemia and pregnancies than in the general population. (6) More- Hyperinsulinemia in Diabetic over, both the stillbirth rate and perinatal mortality in type 1 diabetic pregnancies did not decrease significantly Pregnancies between 1985 and 2004 in Norway. Increased fetal substrate uptake Increased risk of fetal macrosomia Increased risk of fetal shoulder dystocia at delivery Fetal Malformations Increased risk of fetal trauma at delivery (Erb palsy, There is now general agreement that poor maternal gly- fractures) cemic control (hyperglycemia) at conception and during Increased risk of stillbirth at delivery fi Increased risk of neonatal asphyxia at delivery the rst trimester of pregnancy is the main cause of fetal Increased risk of maternal trauma major malformations in diabetic pregnancies. (7)(8)(9)(10) Increased rate of cesarean deliveries Poor glycemic control increases also the miscarriage risk Decreased rate of intrauterine growth restriction in these pregnancies. (7) Hyperglycemia in the develop- Fetal Chronic Hypoxia ing fetus alters lipid metabolism, generates an excess of Increased oxygen consumption and decreased arterial oxygen content reactive oxygen species, and activates apoptosis, which Increased fetal erythropoietin synthesis all can result in fetal malformations. (11) Although the Fetal polycythemia risk of fetal malformations has decreased during the past Increased nucleated red cell count in cord blood 3 decades due to improved glycemic control in women Decreased or depleted fetal iron stores with diabetes, (8) the rate of malformations is still two Increased fetal and neonatal distress and asphyxia Increased risk of stillbirth to four times higher in type 1 and type 2 diabetic preg- Delayed lung maturation nancies than in the general population. (8)(9)(10)(12) Increased risk of neonatal respiratory distress The most common malformations in diabetic preg- syndrome nancies occur in the heart, central nervous system, and Increased risk of neonatal transient tachypnea urinary system. (13) Multiple malformations are also Neonatal hypoglycemia Increased risk of hypoglycemia during the first days common in fetuses of pregestational diabetic women. after birth Caudal regression syndrome, although rare, is seen in diabetic pregnancies only. There is not an increased risk of e84 NeoReviews Vol.15 No.3 March 2014 Downloaded from http://neoreviews.aappublications.org/ at Health Sciences Library, Stony Brook University on February 12, 2015 endocrinology diabetic pregnancy

malformations in the offspring of women with gestational Increasing the insulin dose by 30% to 50% for a few days is diabetes (GDM), although there are reports that the risk often necessary when glucocorticoids are used in diabetic of congenital malformations is slightly increased in pregnancies. (17) women diagnosed with GDM. However, malformations in these pregnancies are likely to occur in hyperglycemic women with undiagnosed type 2 diabetes. Fetal Growth Preconception care is important in type 1 and type 2 di- Fetal overgrowth during the last trimester of pregnancy is abetic pregnancies because fetal malformations are formed the most common fetal complication in pregnancies of early during fetal development, (14) usually before first an- women with diabetes. The birthweight should be ex- tenatal visit. A threefold reduction in the risk of major mal- pressed as relative to the gestational age. Large for gesta- formations has been reported in offspring of women who tional age is best defined as more than 2 SD (>97.7th received prepregnancy care compared with offspring of percentile) above the mean birthweight of a standard women without such care. (15) Unfortunately, approxi- population, but birthweight more than 90th percentile mately half of pregnancies are not planned, and therefore is also frequently used. Small for gestational age is defined only 30% to 40% of the diabetic patients attend a clinic as more than 2 SD (<2.3th percentile) below the refer- for prepregnancy care. Folic acid and vitamin supplemen- ence mean. (20) Ethnicity, genetic, and environmental tation is recommended to all women in reproductive factors (eg, maternal BMI, parity, smoking, and nutri- age. (16) This is especially important in type 1 and type tion) influence the size of the fetus. 2 diabetes patients. At the prepregnancy visit, diabetes Fetal macrosomia is often defined as birthweight more complications should be evaluated, and the risk of preg- than 4,000 g, but the foregoing definition of large for ges- nancy and fetal complications should be discussed in addi- tational age is preferred as the definition for macrosomia. At tion to controlling the glycemic status. (17) Most centers present, 18% of newborn infants weigh more than 4,000 g recommend that the HbA1c should be less than 7% before at birth in Finland. The corresponding figure in the United conception, but this cannot be achieved in all type 1 diabe- States is 9%. In type 1 diabetic pregnancies, the rate of tes patients. The rate of major malformations in offspring of macrosomia defined as more than 2 SD above the mean type 2 diabetic pregnancies does not differ from the rates in of the reference population is more than 30% in Finland offspring of type 1 diabetic pregnancies. (18) and Sweden. (2)(21) The birthweight distribution in type A thorough sonographic examination of the fetal struc- 1 diabetic pregnancies is normal Gaussian but shifted to tures should be offered to all diabetic patients at 18 to 20 the right (22)(23), that is, the number of small for ges- weeks’ gestation. If the glycemic control is not optimal in early tational age fetuses in diabetic pregnancies is lower than pregnancy (HbA1c >8%), a fetal echocardiography is recom- in the general population. In Sweden, 3% of birthweights mended at w20 weeks’ gestation. Even in patients with poor were below the 10th percentile in type 1 diabetic preg- glycemic control in early pregnancy (HbA1c >10%), 85% to nancies compared with 9.1% in the general population. 90% of the fetuses do not have major malformations. (8)(9) (23)

Therefore, a high HbA1c value alone in early pregnancy Fetal hyperinsulinemia is the main cause of fetal over- should not be an indication to interrupt the pregnancy. growth in diabetic pregnancies. (24)(25) Chronic hyperinsulinemia in euglycemic rhesus monkeys results in fetal macrosomia and organomegaly. (24) Interestingly, macro- Preterm Birth somic fetuses of nondiabetic mothers with a birthweight Poor glycemic control (hyperglycemia) has been reported more than 2 SD above the mean of the background pop- to increase the risk of spontaneous preterm birth rate in ulation are not hyperinsulinemic. (25) Fetal body compo- type 1 diabetic pregnancies. (19) Pre-eclampsia and dia- sition of diabetic mothers differs often from fetal body betic nephropathy can cause fetal growth restriction in di- composition of healthy mothers. (26) Macrosomic fe- abetic pregnancies, which increases iatrogenic preterm tuses of diabetic mothers have increased adipose tissue and birth because severe early pre-eclampsia necessitates de- organomegaly, but their head size is not increased. Severe livery on maternal or fetal indications before 30 weeks’ shoulder dystocia can result in brachial plexus injury during gestation. Glucocorticoids also should be used in threat- vaginal delivery, which occurs 10 times more often in ened preterm labor in diabetic pregnancies. However, offspring of type 1 diabetic pregnancies than in the gen- glucocorticoid administration to women with pregestational eral population. (2)(27) The majority of brachial plexus or insulin-treated gestational diabetes can result in injuries and fractures occurs in fetuses weighing more long-lasting hyperglycemia and increased risk of ketoacidosis. than 4,000 g at birth. (28)

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The most accurate method for pregnancy dating is by increased nucleated red cells in cord blood occur also fre- measuring the fetal crown to rump length at w10 to 12 quently in pregestational diabetic pregnancies. (37) The weeks’ gestation. Accurate dating is important when es- fetus adapts to chronic hypoxia by redistributing its car- timating the fetal weight in diabetic pregnancy during the diac output and maintaining its blood flow to the brain last trimester of pregnancy. However, estimating the fetal and heart and by increasing its EPO synthesis to increase weight by sonography has been disappointing. (29) The the oxygen-carrying capacity in the blood. Both elevated mean error in the estimation of fetal weight by sonogra- fetal plasma and amniotic fluid EPO levels are markers of phy is 10% to 15% for normal weight fetuses, but it in- intrauterine chronic hypoxia. (35) Fetal EPO levels are creases to 15% to 20% when predicting birthweights frequently elevated in type 1 diabetic pregnancies, (36) more than 4,000 g. (30) For example, a fetus with an es- which provides evidence that fetal chronic hypoxia often timated weight of 4,000 g by ultrasound can actually complicates these pregnancies. weigh 5,000 g, which can have serious consequences Increased erythropoiesis requires increased amounts for both the mother and the child. Sonographic models of iron. Iron is therefore preferentially absorbed from fe- using three or four fetal biometric measurements are tal iron stores during increased production of red cells. more accurate than methods using abdominal circumfer- (38) The iron stores of stillbirth fetuses of diabetic moth- ence alone or two biometric measurements. (30) ers are extremely low or totally depleted, (39) suggesting Fetal weight, shoulder width, and pelvic capacity can that chronic hypoxia is the main cause of late fetal deaths. be measured using magnetic resonance imaging (MRI), In line with this are the observations that the iron distri- (31)(32)(33) but large clinical studies about the usefulness bution is abnormal and the ferritin levels are low in new- of MRI in obstetrics are still lacking. It is now also possible born infants of diabetic mothers. (39) Fetal chronic to measure fetal fat volume and body composition using hypoxia and associated fetal iron deficiency may be re- MRI. (34) Studies for evaluating the clinical value of MRI sponsible for abnormal neurodevelopment in offspring in detecting fetal macrosomia and abnormal body composi- of diabetic mothers. (40) tionareurgentlyneeded,particularly in diabetic pregnancies. In the fetal sheep, both hyperinsulinemia and hypergly- Fetal growth restriction in diabetic pregnancies occurs cemia result in an increase in fetal oxygen consumption and mainly in women with nephropathy, in whom pre- a fall in arterial oxygen content. (41)(42) Fetal insulin levels eclampsia often further complicates the outcome of their correlate directly with fetal EPO levels in diabetic pregnan- offspring. Because diabetes also increases the birthweight cies, (43) suggesting that hyperinsulinemia also results in of growth-restricted fetuses, it is possible that growth re- fetal chronic hypoxia in human pregnancies. Maternal striction of fetuses of type 1 diabetic women should be HbA1c levels obtained during the last month before deliv- defined differently from pregnancies of nondiabetic preg- ery in type 1 diabetic pregnancies correlates directly with nancies. Amniotic fluid erythropoietin (EPO) is a specific fetal EPO levels, (35)(43) emphasizing the importance of indicator of fetal chronic hypoxia. (35) We have shown maintaining good glycemic control throughout pregnancy. that relative birthweight correlates in a U-shaped fashion Forced stepwise multiple regression analysis has shown that with amniotic fluid EPO concentration in type 1 diabetic both maternal hyperglycemia (ie, fetal hyperglycemia) and pregnancies. (36) Amniotic fluid EPO concentration cor- fetal hyperinsulinemia independently can cause fetal chronic related negatively with birthweight when the birthweight hypoxia as indicated by elevated fetal EPO levels. (43) z score was below –0.6 SD units (r ¼ –0.63, P < .001) The fact that perinatal mortality has not decreased in but positively when the birthweight z score was above diabetic pregnancies in most centers during the past few þ1.0 SD units (r ¼ 0.32, P ¼ .001). (36) This could ex- decades indicates that the current methods and strategies plain why unexpected stillbirths occur also in fetuses with for fetal surveillance are not satisfactory. Twice weekly “normal” birthweight (birthweight z score above –2SD nonstressed testing of FHR has been suggested for pre- but below þ2.0 SD). More studies are clearly needed to vention of stillbirths during the last weeks of pregnancy. evaluate the optimal birthweight in diabetic pregnancies. (44) However, several studies have shown that nonstressed FHR and biophysical testing have limited value in diabetic pregnancies, (45)(46) which is probably ex- Fetal Chronic Hypoxia plained by different pathogenetic mechanism of fetal hyp- Clinical signs of fetal hypoxia (abnormal fetal heart rate oxia in diabetic pregnancies compared with fetal hypoxia [FHR] changes, umbilical artery acidosis, and low Apgar resulting from placental insufficiency. For the same rea- scores at birth) are more common in diabetic than non- son, studies on uterine or umbilical artery Doppler flow diabetic pregnancies. (37) Neonatal polycythemia and assessment have concluded that this method is not e86 NeoReviews Vol.15 No.3 March 2014 Downloaded from http://neoreviews.aappublications.org/ at Health Sciences Library, Stony Brook University on February 12, 2015 endocrinology diabetic pregnancy

reliable in fetal surveillance in diabetic pregnancies with the possible exception of pregnancies complicated by American Board of Pediatrics Neonatal-Perinatal pre-eclampsia or growth restriction. (47) Content Specifications Exponentially increasing EPO levels in the amniotic fluid • Know the effects on the fetus and/or is associated with fetal hypoxia (for review, see Teramo and newborn infant of maternal diabetes 2 Widness). (35) In our own study, abnormal high amniotic mellitus (including gestational diabetes) fluid EPO levels were detected antenatally in 21 of 156 and their management • Know the hormonal factors that affect (13.5%) consecutive type 1 diabetic pregnancies. (36) High intrauterine fetal growth amniotic fluid EPO levels predicted fetal macrosomia (odds ratio [OR] 5.4, 95% confidence interval [CI] 1.9–15.3), obstructive cardiomyopathy (OR 12.5, 95% CI 2.6–59.3), neonatal hypoglycemia (OR 11.3, 95% CI 3.8–33.7) References and NICU admission (OR 3.4%, 95% CI 1.1–10.8). 1. Gabbe SG, Graves CR. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol. 2003;102(4):857–868 (36) Fetal EPO synthesis increases regardless of the eti- 2. Persson M, Norman M, Hanson U. Obstetric and perinatal ology of hypoxia. It is therefore possible to detect fetal outcomes in type 1 diabetic pregnancies: a large, population-based chronic hypoxia antenatally by amniotic fluid EPO mea- study. Diabetes Care. 2009;32(11):2005–2009 surement in type 1 diabetic pregnancies. (35) However, 3. Teramo KA. Obstetric problems in diabetic pregnancy—the role fi of fetal hypoxia. Best Pract Res Clin Endocrinol Metab. 2010;24(4): suf ciently large controlled studies should be performed – fi fl 663 671 before possible clinical bene ts of amniotic uid EPO 4. Hagbard L. Pregnancy and diabetes mellitus; a clinical study. measurements in diabetic pregnancies can be recommended. Acta Obstet Gynecol Scand Suppl. 1956;35(suppl 1):1–180 5. Engel PJ, Smith R, Brinsmead MW, et al. Male sex and pre- existing diabetes are independent risk factors for stillbirth. Aust N Z J Timing and Mode of Delivery Obstet Gynaecol. 2008;48(4):375–383 6. Eidem I, Vangen S, Hanssen KF, et al. Perinatal and infant The American College of Obstetricians and Gynecolo- mortality in term and preterm births among women with type 1 gists recommends elective cesarean delivery when the es- diabetes. Diabetologia. 2011;54(11):2771–2778 timated fetal weight is more than 5,000 g in pregnancies 7. Hanson U, Persson B, Thunell S. Relationship between haemo- of nondiabetic women and when the estimated weight is globin A1C in early type 1 (insulin-dependent) diabetic pregnancy more than 4,500 g in diabetic women. (48) Arrest of de- and the occurrence of spontaneous abortion and fetal malformation in Sweden. Diabetologia. 1990;33(2):100–104 scent of the fetal head or prolonged second stage of labor 8. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control during are also indications for cesarean delivery when the esti- early pregnancy and fetal malformations in women with type I mated fetal weight is more than 4,500 g. Vacuum extrac- diabetes mellitus. Diabetologia. 2000;43(1):79–82 tion and forceps delivery increase the risk of shoulder 9. Jensen DM, Korsholm L, Ovesen P, et al. Peri-conceptional dystocia of macrosomic fetuses in diabetic pregnancies. A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care. 2009;32(6):1046–1048 The proportionally high stillbirth rate in term type 1 10. Murphy HR, Steel SA, Roland JM, et al. Obstetric and diabetic pregnancies has influenced clinical guidelines perinatal outcomes in pregnancies complicated by type 1 and type for timing of delivery. The National Institute for Health 2 diabetes: influence of glycaemic control, obesity and social Care and Excellence guidelines in the United Kingdom disadvantage. Diabet Med. 2011;28(9):1060–1067 recommends that women with pregestational diabetes 11. Reece EA. Diabetes-induced birth defects: what do we know? What can we do? Curr Diab Rep. 2012;12(1):24–32 should be offered induction of labor or elective cesarean 12. Towner D, Kjos SL, Leung B, et al. Congenital malformations ’ delivery at completed 38 weeks pregnancy. (49) The in pregnancies complicated by NIDDM. 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Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mortality has not decreased during the past 30 years, new mellitus: a meta-analysis. QJM. 2001;94(8):435–444 strategies for identifying diabetic pregnancies with a high 16. Wilson RD, Johnson JA, Wyatt P, et al; Genetics Committee of risk of fetal hypoxic complications needs to be developed. the Society of Obstetricians and Gynaecologists of Canada and The

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Motherrisk Program. Pre-conceptional vitamin/folic acid supple- 33. Spörri S, Thoeny HC, Raio L, Lachat R, Vock P, Schneider H. mentation 2007: the use of folic acid in combination with MR imaging pelvimetry: a useful adjunct in the treatment of women a multivitamin supplement for the prevention of neural tube defects at risk for dystocia? AJR Am J Roentgenol. 2002;179(1):137–144 and other congenital anomalies [published correction appears in 34. Anblagan D, Deshpande R, Jones NW, et al. Measurement of J Obstet Gynaecol Can. 2008;30(3):193]. J Obstet Gynaecol Can. fetal fat in utero in normal and diabetic pregnancies using magnetic 2007;29(12):1003–1026 resonance imaging. Ultrasound Obstet Gynecol. 2013;42(3):335–340 17. McCance DR. Pregnancy and diabetes. Best Pract Res Clin 35. Teramo KA, Widness JA. Increased fetal plasma and amniotic Endocrinol Metab. 2011;25(6):945–958 fluid erythropoietin concentrations: markers of intrauterine hyp- 18. 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Effects of diabetic pregnancy on the 1990;33(6):378–383 fetus and newborn. Semin Perinatol. 2000;24(2):120–135 44. Kjos SL, Leung A, Henry OA, Victor MR, Paul RH, Medearis 26. Catalano PM, Thomas A, Huston-Presley L, Amini SB. AL. Antepartum surveillance in diabetic pregnancies: predictors of Increased fetal adiposity: a very sensitive marker of abnormal in fetal distress in labor. Am J Obstet Gynecol. 1995;173(5): utero development. Am J Obstet Gynecol. 2003;189(6):1698–1704 1532–1539 27. Confidential Enquiry into Maternal and Child Health (CEMACH). 45. Devoe LD, Youssef AA, Castillo RA, Croom CS. Fetal Pregnancy in Women With Type 1 and Type 2 Diabetes in 2002–2003, biophysical activities in third-trimester pregnancies complicated by England, Wales and Northern Ireland.London,UK:CHEMACH; diabetes mellitus. Am J Obstet Gynecol. 1994;171(2):298–303, 2005 discussion 303–305 28. Bjørstad AR, Irgens-Hansen K, Daltveit AK, Irgens LM. 46. Tincello D, White S, Walkinshaw S. Computerised analysis of Macrosomia: mode of delivery and pregnancy outcome. Acta fetal heart rate recordings in maternal type 1 diabetes mellitus. Br J Obstet Gynecol Scand. 2010;89(5):664–669 Obstet Gynaecol. 2001;108:853–857 29. Chauhan SP, Charania SF, McLaren RA, et al. Ultrasono- 47. Wong SF, Chan FY, Cincotta RB, McIntyre DH, Stone M. graphic estimate of birth weight at 24 to 34 weeks: a multicenter Use of umbilical artery Doppler velocimetry in the monitoring of study. Am J Obstet Gynecol. 1998;179(4):909–916 pregnancy in women with pre-existing diabetes. Aust N Z J Obstet 30. Melamed N, Yogev Y, Meizner I, Mashiach R, Pardo J, Ben- Gynaecol. 2003;43(4):302–306 Haroush A. Prediction of fetal macrosomia: effect of sonographic 48. American College of Obstetricians and Gynecologists. Fetal fetal weight-estimation model and threshold used. Ultrasound Macrosomia. ACOG Practice Bulletin Number 22. 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1. A mother who has history of diabetes controlled by insulin is pregnant and asks about the risk of fetal malformations. Which of the following statements regarding risk of fetal malformation in diabetic pregnancy is correct? A. The highest risk of a major malformation occurs when there is poor maternal glycemic control during the second and third trimesters. B. The rate of malformation is two to four times higher in type 1 and type 2 pregnancies than in the general population. C. The most common malformations in diabetic pregnancies involve the upper and lower extremities. D. The risk of malformations in gestational diabetes is equal to the risk found in type 1 and type 2 diabetes. E. Unlike typical pregnancies, folic acid should be avoided in pregnant women with type 1 diabetes, as the risk of folic acid excess is higher than that of neural tube defects.

2. A 28-year-old woman is pregnant with her second child. Her ﬁrst pregnancy resulted in a spontaneous preterm delivery at 28 weeks’ gestational age. Her second pregnancy is complicated by diabetes. Which of the following is true regarding her risk of preterm birth? A. One risk of preeclampsia and diabetic nephropathy is fetal growth restriction, which may increase the risk of iatrogenic preterm birth, if there are fetal indications. B. As her ﬁrst child was born preterm, it is highly unlikely that she will have a second preterm child, as one mother having two preterm births in a row is a rare occurrence. C. Spontaneous preterm birth is most likely to be an increased occurrence in gestational diabetes, as compared to type 1 diabetic pregnancies. D. If preterm birth is likely to occur, it is important to remember that glucocorticoids are contraindicated in diabetic mothers. E. While preterm birth is an increased risk in diabetic pregnancies, late preterm birth is generally more acceptable than non-diabetic pregnancies, as these infants tend to be larger and more mature for their gestational age.

3. A pregnant woman with diabetes is evaluated at 35 weeks’ gestational age. Fetal growth parameters are estimated using physical examination and ultrasound. Which of the following statements regarding growth in diabetic pregnancies is correct? A. Ultrasound estimate of fetal weight is more accurate in diabetic pregnancies than in non-diabetics due, particularly in larger fetuses more than 4,000 grams, as there is a higher ratio of solid mass to ﬂuid. B. Fetal hyperinsulinemia is the main cause of fetal overgrowth in diabetic pregnancies. C. The most accurate method for pregnancy dating is fetal crown-rump length at 18 to 20 weeks’ gestational age. D. Although macrosomia is more common in type 1 diabetic pregnancies at 18% to 30%, the incidence of small for gestational age is also increased to 10% to 25%. E. In macrosomic infants of diabetic mothers, the head size is disproportionately increased up to 30% of normal size, compounding risk of delivery problems.

4. A 39-week-gestational-age male infant is born by spontaneous vaginal delivery to a mother who had gestational diabetes which was diet controlled. He develops respiratory distress and an evaluation includes hematocrit which is noted to be 72% two hours after birth. Which of the following statements regarding this clinical circumstance is correct? A. A hematocrit at age 2 hours is more reﬂective of the mother’s hematocrit and should not be considered as part of the diagnostic work-up of an infant.

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B. While polycythemia can occur in type 1 diabetic pregnancies, it is not associated with gestational diabetes and is likely to arise from a different etiology in this scenario. C. This infant may have had some degree of chronic hypoxia and increased erythropoietin synthesis in order to increase oxygen carrying capacity. D. This infant’s ferritin levels are likely to be abnormally elevated. E. Erythropoietin would have been rapidly consumed by this fetus and if an amniotic ﬂuid sample was obtained before delivery, it is likely that erythropoietin levels in the ﬂuid would be low or non-existent.

5. A mother presents with intermittent contractions to the clinic at 40 weeks’ gestational age. She has gestational diabetes which has been poorly controlled, and is suspected to have risk of a macrosomic fetus based on recent visits. Which of the following regarding her delivery course and management is correct? A. Although her infant may be macrosomic, the risks of non-spontaneous labor induction on respiratory outcomes balance out risks of macrosomia, and therefore, delivery should be deferred until spontaneous labor or induction at 41 weeks. B. Fetal weight estimates should not have a role in decisions about mode of delivery due to their inaccuracy. C. While cesarean delivery is more common in diabetic pregnancies, they can be avoided in situations when the infant is mildly macrosomic (>4,500–5,000 grams) with vacuum extraction or forceps assistance, with decreased risk of shoulder dystocia. D. Cesarean delivery is probably indicated when the estimated fetal weight is more than 4,500 grams and there is arrest of descent of the head or a prolonged second stage of labor. E. A key principle in the management of diabetic mothers is to disregard estimated fetal weight in the decision to perform cesarean section due to its inaccuracy and lack of ability to predict clinical complications.

Parent Resources from the AAP at HealthyChildren.org

• English: http://www.healthychildren.org/English/ages-stages/prenatal/Pages/Tests-During-Pregnancy.aspx • Spanish: http://www.healthychildren.org/spanish/ages-stages/prenatal/paginas/tests-during-pregnancy.aspx

e90 NeoReviews Vol.15 No.3 March 2014 Downloaded from http://neoreviews.aappublications.org/ at Health Sciences Library, Stony Brook University on February 12, 2015 Diabetic Pregnancy and Fetal Consequences Kari Teramo NeoReviews 2014;15;e83 DOI: 10.1542/neo.15-3-e83

Updated Information & including high resolution figures, can be found at: Services http://neoreviews.aappublications.org/content/15/3/e83 References This article cites 48 articles, 11 of which you can access for free at: http://neoreviews.aappublications.org/content/15/3/e83#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Diabetes Mellitus http://neoreviews.aappublications.org/cgi/collection/diabetes_mellitu s_sub Endocrinology http://neoreviews.aappublications.org/cgi/collection/endocrinology_s ub Gynecology http://neoreviews.aappublications.org/cgi/collection/gynecology_sub Maternal and Fetal Medicine http://neoreviews.aappublications.org/cgi/collection/maternal_fetal_ medicine_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://neoreviews.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://neoreviews.aappublications.org/site/misc/reprints.xhtml

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